Abstract:

To date, there is rapidly growing evidence that the intestinal microbiota interacts with the host at many different levels to regulate physiology. The discovery that changes in the composition of the gut microbiota correlates with alteration in brain and behaviour has largely contributed to the extension of the well characterized gut-brain axis to encompass the intestinal microbiota as a partner in gut-brain signalling, coining the term microbiota-gut-brain axis. Understanding the impact of the gut microbiota on host health and the potential mechanisms mediating these changes have largely relied on preclinical models of microbiota manipulation. Proof-of principal experiments using germ-free (GF) animals have been instrumental in establishing our current understanding of host-microbe interaction and the impact on behaviour, especially related to anxiety. This thesis investigates the underlying transcriptional changes in GF mice in key brain structures such as the amygdala and prefrontal cortex (PFC) in order to identify molecular pathways that may underlie the observed behavioural phenotype in these animals. To compliment this, we further investigated whether post-transcriptional regulatory mechanisms are recruited by the gut microbiota. Indeed, we find unique transcriptional and posttranscriptional profiles in these brain regions in GF animals and microbiota depleted animals. These findings reinforce the concept that microbes act at the molecular level to influence development and function of the amygdala and PFC, which are critical for feelings of fear and anxiety. Here we show, to our knowledge, what is the first demonstration that the microbiota is key for normal cortical myelination. Further efforts into understanding the interaction between microbes and CNS myelination may allow the development of strategies to promote remyelination in disorders of demyelination like multiple sclerosis. To further interrogate the importance of the gut microbiota in amygdala dependent behaviours we investigated whether absence of the intestinal microbiota impacted fear memory learning. We demonstrate that life without microbes results in impairments in amygdala dependent learning. Finally, this thesis demonstrates that targeted depletion of the gut microbiota in adulthood, after normal microbial assembly dramatically reshapes the behavioural and neurochemical profile and results in cognitive impairments, increased depressive-like behaviours and visceral hypersensitivity. Overall this thesis has greatly contributed to our current knowledge surrounding the importance of functional microbiota-gut-brain axis signalling and implicates the gut microbiota as a novel target for regulating cortical myelination, controlling transcriptional pathways in the amygdala and the associated expression of anxiety-like behaviours. These studies have implications for a range of neuropsychiatric disorders and lay the groundwork for therapeutic targeting of the gut microbiota.

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